LAMIVUDINE TEVA 100mg tablets medication leaflet

Lamivudine Teva 100 mg film-coated tablets

Each film-coated tablet contains 100 mg lamivudine

For the full list of excipients, see section 6.1.

Film-coated tablet

Orange, capsule shaped, biconvex film-coated tablet - engraved with “L 100” on one side and plain onthe other.

Lamivudine Teva is indicated for the treatment of chronic hepatitis B in adults with:

* compensated liver disease with evidence of active viral replication, persistently elevated serumalanine aminotransferase (ALT) levels and histological evidence of active liver inflammation and/ or fibrosis. Initiation of lamivudine treatment should only be considered when the use of analternative antiviral agent with a higher genetic barrier is not available or appropriate (see section5.1).

* decompensated liver disease in combination with a second agent without cross-resistance tolamivudine (see section 4.2).

Therapy with Lamivudine Teva should be initiated by a physician experienced in the management ofchronic hepatitis B.

The recommended dosage of Lamivudine Teva is 100 mg once daily.

In patients with decompensated liver disease, lamivudine should always be used in combination with asecond agent, without cross-resistance to lamivudine, to reduce the risk of resistance and to achieverapid viral suppression.

The optimal duration of treatment is unknown.

* In patients with HBeAg positive chronic hepatitis B (CHB) without cirrhosis, treatment should beadministered for at least 6-12 months after HBeAg seroconversion (HBeAg and HBV DNA losswith HBeAb detection) is confirmed, to limit the risk of virological relapse, or until HBsAgseroconversion or there is loss of efficacy (see section 4.4). Serum ALT and HBV DNA levelsshould be followed regularly after treatment discontinuation to detect any late virological relapse.

* In patients with HBeAg negative CHB (pre-core mutant) without cirrhosis, treatment should beadministered at least until HBs seroconversion or there is evidence of loss of efficacy. Withprolonged treatment, regular reassessment is recommended to confirm that continuation of theselected therapy remains appropriate for the patient.

* In patients with decompensated liver disease or cirrhosis and in liver transplant recipients,treatment cessation is not recommended (see section 5.1).

If lamivudine is discontinued, patients should be periodically monitored for evidence of recurrenthepatitis (see section 4.4).

Clinical resistance

In patients with either HBeAg positive or HBeAg negative CHB, the development of YMDD(tyrosine-methionine-aspartate-aspartate) mutant HBV may result in a diminished therapeutic responseto lamivudine, indicated by a rise in HBV DNA and ALT from previous on-treatment levels. In orderto reduce the risk of resistance in patients receiving lamivudine monotherapy, a switch to or additionof an alternative agent without cross-resistance to lamivudine based on therapeutic guidelines shouldbe considered if serum HBV DNA remains detectable at or beyond 24 weeks of treatment (see section5.1).

Lamivudine serum concentrations (AUC) are increased in patients with moderate to severe renalimpairment due to decreased renal clearance. The dosage should therefore be reduced for patients witha creatinine clearance of < 50 ml/minute. Lamivudine Teva is not suitable for patients who requiredoses below 100 mg.

Data available in patients undergoing intermittent haemodialysis (for less than or equal to 4 hrsdialysis 2-3 times weekly), indicate that following the initial dosage reduction of lamivudine to correctfor the patient’s creatinine clearance, no further dosage adjustments are required while undergoingdialysis.

Data obtained in patients with hepatic impairment, including those with end-stage liver diseaseawaiting transplant, show that lamivudine pharmacokinetics are not significantly affected by hepaticdysfunction. Based on these data, no dose adjustment is necessary in patients with hepatic impairmentunless accompanied by renal impairment.

HIV co-infection

For the treatment of patients who are co-infected with HIV and are currently receiving or plan toreceive combined antiretroviral treatment including lamivudine, the dose of lamivudine prescribed for

HIV infection (usually 150 mg/twice daily in combination with other antiretrovirals) should be used.

In elderly patients, normal ageing with accompanying renal decline has no clinically significant effecton lamivudine exposure, except in patients with creatinine clearance of < 50 ml/min.

The safety and efficacy of Lamivudine Teva in infants, children and adolescents aged below 18 yearshave not been established. Currently available data are described in sections 4.4 and 5.1 but norecommendation on a posology can be made.

Oral use.

Lamivudine Teva can be taken with or without food.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Exacerbations of hepatitis

Exacerbations on treatment

Spontaneous exacerbations in chronic hepatitis B are relatively common and are characterised bytransient increases in serum ALT. After initiating antiviral therapy, serum ALT may increase in somepatients as serum HBV DNA levels decline. In patients with compensated liver disease, these increasesin serum ALT were generally not accompanied by an increase in serum bilirubin concentrations orsigns of hepatic decompensation.

HBV viral subpopulations with reduced susceptibility to lamivudine (YMDD mutant HBV) have beenidentified with extended therapy. In some patients the development of YMDD mutant HBV can lead toexacerbation of hepatitis, primarily detected by serum ALT elevations and re-emergence of HBV

DNA (see section 4.2). In patients who have YMDD mutant HBV, a switch to or addition of analternative agent without cross resistance to lamivudine based on therapeutic guidelines should beconsidered (see section 5.1).

Exacerbations after treatment discontinuation

Acute exacerbation of hepatitis has been observed in patients who have discontinued hepatitis Btherapy and is usually detected by serum ALT elevations and re-emergence of HBV DNA. In thecontrolled Phase III trials with no-active-treatment follow-up, the incidence of post-treatment ALTelevations (more than 3 times baseline) was higher in lamivudine-treated patients (21%) comparedwith those receiving placebo (8%). However, the proportion of patients who had post-treatmentelevations associated with bilirubin elevations was low and similar in both treatment arms (see Table 3in section 5.1). For lamivudine-treated patients, the majority of post-treatment ALT elevationsoccurred between 8 and 12 weeks post-treatment. Most events have been self-limiting, however somefatalities have been observed. If Lamivudine Teva is discontinued, patients should be periodicallymonitored both clinically and by assessment of serum liver function tests (ALT and bilirubin levels),for at least four months, and then as clinically indicated.

Exacerbations in patients with decompensated cirrhosis

Transplantation recipients and patients with decompensated cirrhosis are at greater risk from activeviral replication. Due to the marginal liver function in these patients, hepatitis reactivation atdiscontinuation of lamivudine or loss of efficacy during treatment may induce severe and even fataldecompensation. These patients should be monitored for clinical, virological and serologicalparameters associated with hepatitis B, liver and renal function, and antiviral response duringtreatment (at least every month), and, if treatment is discontinued for any reason, for at least 6 monthsafter treatment. Laboratory parameters to be monitored should include (as a minimum) serum ALT,bilirubin, albumin, blood urea nitrogen, creatinine, and virological status: HBV antigen/antibody, andserum HBV DNA concentrations when possible. Patients experiencing signs of hepatic insufficiencyduring or post-treatment should be monitored more frequently as appropriate.

For patients who develop evidence of recurrent hepatitis post-treatment, there are insufficient data onthe benefits of re-initiation of lamivudine treatment.

Nucleoside and nucleotide analogues have been demonstrated in vitro and in vivo to cause a variabledegree of mitochondrial damage. There have been reports of mitochondrial dysfunction in infantsexposed in utero and/or post-natally to nucleoside analogues. The main adverse events reported arehaematological disorders (anaemia, neutropenia), metabolic disorders (hyperlipasemia). Some late-onset neurological disorders have been reported (hypertonia, convulsion, abnormal behaviour). Theneurological disorders might be transient or permanent. Any child exposed in utero to nucleoside andnucleotide analogues, should have clinical and laboratory follow-up and should be fully investigatedfor possible mitochondrial dysfunction in cases which have relevant signs or symptoms.

Lamivudine has been administered to children (2 years and above) and adolescents with compensatedchronic hepatitis B. However, due to limitations of the data, the administration of lamivudine to thispatient population is not currently recommended (see section 5.1).

Delta hepatitis or hepatitis C

The efficacy of lamivudine in patients co-infected with Delta hepatitis or hepatitis C has not beenestablished and caution is advised.

Immunosuppressive treatments

Data are limited on the use of lamivudine in HBeAg negative (pre-core mutant) patients and in thosereceiving concurrent immunosuppressive regimes, including cancer chemotherapy. Lamivudine shouldbe used with caution in these patients.

During treatment with Lamivudine Teva patients should be monitored regularly. Serum ALT and HBV

DNA levels should be monitored at 3 month intervals and in HBeAg positive patients HBeAg shouldbe assessed every 6 months.

HIV co-infection

For the treatment of patients who are co-infected with HIV and are currently receiving or plan toreceive treatment with an antiretroviral combination regimen including lamivudine, the dose oflamivudine prescribed for HIV infection (usually 150 mg/twice daily in combination with otherantiretrovirals) should be used.

The 100 mg usual dose of lamivudine used for the treatment of HBV is not appropriate for patientswho acquire HIV or are co-infected with HBV and HIV. If a patient with unrecognised or untreated

HIV infection is prescribed the dose of lamivudine recommended for the treatment of HBV, rapidemergence of HIV resistance and a limitation of treatment options is likely to result because of thesubtherapeutic dose and the inappropriate use of monotherapy for HIV treatment. HIV counselling andtesting should be offered to all patients before beginning treatment with lamivudine for HBV andperiodically during treatment.

Transmission of hepatitis B

There is no information available on maternal-foetal transmission of hepatitis B virus in pregnantwomen receiving treatment with lamivudine. The standard recommended procedures for hepatitis Bvirus immunisation in infants should be followed.

Patients should be advised that therapy with lamivudine has not been proven to reduce the risk oftransmission of hepatitis B virus to others and therefore, appropriate precautions should still be taken.

Lamivudine Teva should not be taken with any other medicinal products containing lamivudine ormedicinal products containing emtricitabine (see section 4.5).

The combination of lamivudine with cladribine is not recommended (see section 4.5).

Excipient

This medicinal product contains less than 1 mmol sodium (23 mg) per film-coated tablet, that is to sayessentially “sodium-free”.

Interaction studies have only been performed in adults.

The likelihood of metabolic interactions is low due to limited metabolism and plasma protein bindingand almost complete renal elimination of unchanged substance.

Lamivudine is predominantly eliminated by active organic cationic secretion. The possibility ofinteractions with other medicinal products administered concurrently should be considered,particularly when their main route of elimination is active renal secretion via the organic cationictransport system e.g. trimethoprim. Other medicinal products (e.g. ranitidine, cimetidine) areeliminated only in part by this mechanism and were shown not to interact with lamivudine.

Substances shown to be predominately excreted either via the active organic anionic pathway, or byglomerular filtration are unlikely to yield clinically significant interactions with lamivudine.

Administration of trimethoprim/sulphamethoxazole 160 mg/800 mg increased lamivudine exposure byabout 40 %. Lamivudine had no effect on the pharmacokinetics of trimethoprim or sulphamethoxazole.

However, unless the patient has renal impairment, no dosage adjustment of lamivudine is necessary.

A modest increase in Cmax (28 %) was observed for zidovudine when administered with lamivudine,however overall exposure (AUC) was not significantly altered. Zidovudine had no effect on thepharmacokinetics of lamivudine (see section 5.2).

Lamivudine has no pharmacokinetic interaction with alpha-interferon when the two medicinalproducts are concurrently administered. There were no observed clinically significant adverseinteractions in patients taking lamivudine concurrently with commonly used immunosuppressantmedicinal products (e.g. cyclosporin A). However, formal interaction studies have not been performed.

Due to similarities, Lamivudine Teva should not be administered concomitantly with other cytidineanalogues, such as emtricitabine. Moreover, Lamivudine Teva should not be taken with any othermedicinal products containing lamivudine (see section 4.4).

Cladribine

In vitro lamivudine inhibits the intracellular phosphorylation of cladribine leading to a potential risk ofcladribine loss of efficacy in case of combination in the clinical setting. Some clinical findings alsosupport a possible interaction between lamivudine and cladribine. Therefore, the concomitant use oflamivudine with cladribine is not recommended (see section 4.4).

Sorbitol

Co-administration of sorbitol solution (3.2 g, 10.2 g, 13.4 g) with a single 300 mg dose (Adult HIVdaily dose) of lamivudine oral solution resulted in dose-dependent decreases of 14%, 32%, and 36% inlamivudine exposure (AUC∞) and 28%, 52%, and 55% in the Cmax of lamivudine in adults. Whenpossible, avoid chronic co-administration of Lamivudine Teva with medicinal products containingsorbitol or other osmotic acting poly-alcohols or monosaccharide alcohols (e.g. xylitol, mannitol,lactitol, maltitol). Consider more frequent monitoring of HBV viral load when chronic co-administration cannot be avoided.

Animal studies with lamivudine showed an increase in early embryonic deaths in rabbits but not in rats(see section 5.3). Placental transfer of lamivudine has been shown to occur in humans.

Available human data from the Antiretroviral Pregnancy Registry reporting more than 1000 outcomesfrom first trimester and more than 1000 outcomes from second and third trimester exposure inpregnant women indicate no malformative and foeto/neonatal effect. Less than 1% of these womenhave been treated for HBV, whereas the majority was treated for HIV at higher doses and with otherconcomitant medications. Lamivudine Teva can be used during pregnancy if clinically needed.

For patients who are being treated with lamivudine and subsequently become pregnant considerationshould be given to the possibility of a recurrence of hepatitis on discontinuation of lamivudine.

Based on more than 200 mother/child pairs treated for HIV, serum concentrations of lamivudine inbreastfed infants of mothers treated for HIV are very low ( less than 4% of maternal serumconcentrations) and progressively decrease to undetectable levels when breastfed infants reach 24weeks of age. The total amount of lamivudine ingested by a breastfed infant is very low and istherefore likely to result in exposures exerting a sub-optimal antiviral effect. Maternal hepatitis B isnot a contraindication to breast-feeding if the newborn is adequately managed for hepatitis Bprevention at birth, and there is no evidence that the low concentration of lamivudine in human milkleads to adverse reactions in breastfed infants. Therefore breastfeeding may be considered in breast-feeding mothers being treated with lamivudine for HBV taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman. Where there is maternal transmission of

HBV, despite adequate prophylaxis, consideration should be given to discontinuing breastfeeding toreduce the risk of the emergence of lamivudine resistant mutants in the infant.

Reproductive studies in animals have shown no effect on male or female fertility (see section 5.3).

Nucleoside and nucleotide analogues have been demonstrated in vitro and in vivo to cause a variabledegree of mitochondrial damage. There have been reports of mitochondrial dysfunction in infantsexposed in utero and/or post-natally to nucleoside analogues (see section 4.4).

Patients should be informed that malaise and fatigue have been reported during treatment withlamivudine. The clinical status of the patient and the adverse reaction profile of lamivudine should beborne in mind when considering the patient's ability to drive or operate machinery.

The incidence of adverse reactions and laboratory abnormalities (with the exception of elevations of

ALT and CPK, see below) were similar between placebo and lamivudine treated patients). The mostcommon adverse reactions reported were malaise and fatigue, respiratory tract infections, throat andtonsil discomfort, headache, abdominal discomfort and pain, nausea, vomiting and diarrhoea.

Adverse reactions are listed below by system organ class and frequency. Frequency categories are onlyassigned to those adverse reactions considered to be at least possibly causally related to lamivudine.

Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000) and not known (cannot be estimatedfrom the available data).

The frequency categories assigned to the adverse reactions are mainly based on experience fromclinical trials including a total of 1,171 patients with chronic hepatitis B receiving lamivudine at100 mg.

Not known Thrombocytopenia

Very rare Lactic acidosis

Rare Angioedema

Very common ALT elevations (see section 4.4)

Exacerbations of hepatitis, primarily detected by serum ALT elevations, have been reported ‘on-treatment’ and following lamivudine withdrawal. Most events have been self-limited, howeverfatalities have been observed very rarely (see section 4.4).

Common Rash, pruritus

Common Elevations of CPK

Common Muscle disorders, including myalgia and cramps*

Not known Rhabdomyolysis

* In Phase III studies frequency observed in the lamivudine treatment group was not greater thanobserved in the placebo group

Based on limited data in children aged 2 to 17 years, there were no new safety issues identifiedcompared to adults.

In patients with HIV infection, cases of pancreatitis and peripheral neuropathy (or paresthesia) havebeen reported. In patients with chronic hepatitis B there was no observed difference in incidence ofthese events between placebo and lamivudine treated patients.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

No specific signs or symptoms have been identified following acute overdose with lamivudine, apartfrom those listed as adverse reactions.

If overdose occurs the patient should be monitored and standard supportive treatment applied asrequired. Since lamivudine is dialysable, continuous haemodialysis could be used in the treatment ofoverdose, although this has not been studied.

Pharmacotherapeutic group - Antivirals for systemic use, nucleoside and nucleotide reversetranscriptase inhibitors,ATC Code: J05AF05.

Lamivudine is an antiviral agent which is active against hepatitis B virus in all cell lines tested and inexperimentally infected animals.

Lamivudine is metabolised by both infected and uninfected cells to the triphosphate (TP) derivativewhich is the active form of the parent compound. The intracellular half-life of the triphosphate inhepatocytes is 17-19 hours in vitro. Lamivudine-TP acts as a substrate for the HBV viral polymerase.

The formation of further viral DNA is blocked by incorporation of lamivudine-TP into the chain andsubsequent chain termination.

Lamivudine-TP does not interfere with normal cellular deoxynucleotide metabolism. It is also only aweak inhibitor of mammalian DNA polymerases alpha and beta. Furthermore, lamivudine-TP has littleeffect on mammalian cell DNA content.

In assays relating to potential substance effects on mitochondrial structure and DNA content andfunction, lamivudine lacked appreciable toxic effects. It has a very low potential to decreasemitochondrial DNA content, is not permanently incorporated into mitochondrial DNA, and does notact as an inhibitor of mitochondrial DNA polymerase gamma.

Experience in patients with HBeAg positive CHB and compensated liver disease

In controlled studies, 1 year of lamivudine therapy significantly suppressed HBV DNA replication[34-57 % of patients were below the assay detection limits (Abbott Genostics solution hybridizationassay, LLOD < 1.6 pg/ml)}, normalised ALT level (40-72 % of patients), induced HBeAgseroconversion (HBeAg loss and HBeAb detection with HBV DNA loss [by conventional assay],16-18 % of patients), improved histology (38-52 % of patients had a ≥ 2 point decrease in the Knodell

Histologic Activity Index [HAI]) and reduced progression of fibrosis (in 3-17 % of patients) andprogression to cirrhosis.

Continued lamivudine treatment for an additional 2 years in patients who had failed to achieve HBeAgseroconversion in the initial 1 year controlled studies resulted in further improvement in bridgingfibrosis. In patients with YMDD mutant HBV, 41/82 (50 %) patients had improvement in liverinflammation and 40/56 (71 %) patients without YMDD mutant HBV had improvement. Improvementin bridging fibrosis occurred in 19/30 (63 %) patients without YMDD mutant and 22/44 (50 %)patients with the mutant. Five percent (3/56) of patients without the YMDD mutant and 13 % (11/82)of patients with YMDD mutant showed worsening in liver inflammation compared to pre-treatment.

Progression to cirrhosis occurred in 4/68 (6 %) patients with the YMDD mutant, whereas no patientswithout the mutant progressed to cirrhosis.

In an extended treatment study in Asian patients (NUCB3018) the HBeAg seroconversion rate and

ALT normalisation rate at the end of the 5 year treatment period was 48 % (28/58) and 47 % (15/32),respectively. HBeAg seroconversion was increased in patients with elevated ALT levels; 77 % (20/26)of patients with pre-treatment ALT > 2 x ULN seroconverted. At the end of 5 years, all patients had

HBV DNA levels that were undetectable or lower than pre-treatment levels.

Further results from the trial by YMDD mutant status are summarised in Table 1.

Table 1: Efficacy results 5 years by YMDD status (Asian Study) NUCB3018

Subjects, % (no.)

YMDD mutant HBV status YMDD1 Non-YMDD1

HBeAg seroconversion

- All patients 38 (15/40) 72 (13/18)

- Baseline ALT ≤ 1 x ULN2 9 (1/11) 33 (2/6)

- Baseline ALT > 2 x ULN 60 (9/15) 100 (11/11)

Undetectable HBV DNA

- Baseline3 5 (2/40) 6 (1/18)

- Week 2604negative 8 (2/25) 0positive < baseline 92 (23/25) 100 (4/4)positive > baseline 0 0

ALT normalisation

- Baselinenormal 28 (11/40) 33 (6/18)above normal 73 (29/40) 67 (12/18)

- Week 260normal 46 (13/28) 50 (2/4)above normal < baseline 21 (6/28) 0above normal > baseline 32 (9/28) 50 (2/4)1 Patients designated as YMDD mutant were those with ≥5 % YMDD mutant HBV at any annual time-point during the 5-year period.

Patients categorised as non-YMDD mutant were those with > 95 % wild-type HBV at all annual time-points during the 5-year study period2 Upper limit of normal3 Abbott Genostics solution hybridisation assay (LLOD < 1.6 pg/ml4 Chiron Quantiplex assay (LLOD 0.7 Meq/ml)

Comparative data according to YMDD status were also available for histological assessment but onlyup to three years. In patients with YMDD mutant HBV, 18/39 (46 %) had improvements innecroinflammatory activity and 9/39 (23 %) had worsening. In patients without the mutant, 20/27(74 %) had improvements in necroinflammatory activity and 2/27 (7 %) had worsening.

Following HBeAg seroconversion, serologic response and clinical remission are generally durableafter stopping lamivudine. However, relapse following seroconversion can occur. In a long-termfollow-up study of patients who had previously seroconverted and discontinued lamivudine, latevirological relapse occurred in 39 % of the subjects. Therefore, following HBeAg seroconversion,patients should be periodically monitored to determine that serologic and clinical responses are beingmaintained. In patients who do not maintain a sustained serological response, consideration should begiven to retreatment with either lamivudine or an alternative antiviral agent for resumption of clinicalcontrol of HBV.

In patients followed for up to 16 weeks after discontinuation of treatment at one year, post-treatment

ALT elevations were observed more frequently in patients who had received lamivudine than inpatients who had received placebo. A comparison of post-treatment ALT elevations between weeks 52and 68 in patients who discontinued lamivudine at week 52 and patients in the same studies whoreceived placebo throughout the treatment course is shown in Table 2. The proportion of patients whohad post-treatment ALT elevations in association with an increase in bilirubin levels was low andsimilar in patients receiving either lamivudine or placebo.

Table 2: Post-treatment ALT Elevations in 2 Placebo-Controlled Studies in Adults

Patients with ALT Elevation/

Patients with Observations*

Abnormal Value Lamivudine Placebo

ALT ≥ 2 x baseline value 37/137 (27 %) 22/116 (19 %)

ALT ≥ 3 x baseline value† 29/137 (21 %) 9/116 (8 %)

ALT ≥ 2 x baseline value and absolute ALT > 500

IU/l 21/137 (15 %) 8/116 (7 %)

ALT ≥2 x baseline value; and bilirubin >2 x ULNand ≥2 x baseline value 1/137 (0.7 %) 1/116 (0.9 %)†*Each patient may be represented in one or more category.

Comparable to a Grade 3 toxicity in accordance with modified WHO criteria.

ULN = Upper limit of normal.

Experience in patients with HBeAg negative CHB:

Initial data indicate the efficacy of lamivudine in patients with HBeAg negative CHB is similar topatients with HBeAg positive CHB, with 71 % of patients having HBV DNA suppressed below thedetection limit of the assay, 67 % ALT normalisation and 38 % with improvement in HAI after oneyear of treatment. When lamivudine was discontinued, the majority of patients (70 %) had a return ofviral replication. Data is available from an extended treatment study in HBeAg negative patients(NUCAB3017) treated with lamivudine. After two years of treatment in this study, ALT normalisationand undetectable HBV DNA occurred in 30/69 (43 %) and 32/68 (47 %) patients respectively andimprovement in necroinflammatory score in 18/49 (37 %) patients. In patients without YMDD mutant

HBV, 14/22 (64 %) showed improvement in necroinflammatory score and 1/22 (5 %) patientsworsened compared to pre-treatment. In patients with the mutant, 4/26 (15 %) patients showedimprovement in necroinflammatory score and 8/26 (31 %) patients worsened compared to pre-treatment. No patients in either group progressed to cirrhosis.

Frequency of emergence of YMDD mutant HBV and impact on the treatment response:

Lamivudine monotherapy results in the selection of YMDD mutant HBV in approximately 24 % ofpatients following one year of therapy, increasing to 69 % following 5 years of therapy. Developmentof YMDD mutant HBV is associated with reduced treatment response in some patients, as evidencedby increased HBV DNA levels and ALT elevations from previous on-therapy levels, progression ofsigns and symptoms of hepatitis disease and/or worsening of hepatic necroinflammatory findings.

Given the risk of YMDD mutant HBV, maintenance of lamivudine monotherapy is not appropriate inpatients with detectable serum HBV DNA at or beyond 24 weeks of treatment (see section 4.4).

In a double-blind study in CHB patients with YMDD mutant HBV and compensated liver disease(NUC20904), with a reduced virological and biochemical response to lamivudine (n=95), the additionof adefovir dipivoxil 10 mg once daily to ongoing lamivudine 100 mg for 52 weeks resulted in amedian decrease in HBV DNA of 4.6 log10 copies/ml compared to a median increase of 0.3log10 copies/ml in those patients receiving lamivudine monotherapy. Normalisation of ALT levelsoccurred in 31 % (14/45) of patients receiving combined therapy versus 6 % (3/47) receivinglamivudine alone. Viral suppression was maintained (follow-on study NUC20917) with combinedtherapy during the second year of treatment to week 104 with patients having continued improvementin virologic and biochemical responses.

In a retrospective study to determine the factors associated with HBV DNA breakthrough, 159 Asian

HBeAg-positive patients were treated with lamivudine and followed up for a median period of almost30 months. Those with HBV DNA levels greater than 200 copies/mL at 6 months (24 weeks) oflamivudine therapy had a 60 % chance of developing the YMDD mutant compared with 8 % of thosewith HBV DNA levels less than 200 copies/mL at 24 weeks of lamivudine therapy. The risk fordeveloping YMDD mutant was 63% versus 13% with a cut off of 1000 copies/ml (NUCB3009 and

NUCB3018).

Experience in patients with decompensated liver disease:

Placebo controlled studies have been regarded as inappropriate in patients with decompensated liverdisease, and have not been undertaken. In non-controlled studies, where lamivudine was administeredprior to and during transplantation, effective HBV DNA suppression and ALT normalisation wasdemonstrated. When lamivudine therapy was continued post transplantation there was reduced graftre-infection by HBV, increased HBsAg loss and on one-year survival rate of 76-100 %.

As anticipated due to the concomitant immunosuppression, the rate of emergence of YMDD mutant

HBV after 52 weeks treatment was higher (36 %-64 %) in the liver transplant population than in theimmunocompetent CHB patients (14 %-32 %).

Forty patients (HBeAg negative or HBeAg positive) with either decompensated liver disease orrecurrent HBV following liver transplantation and YMDD mutant were enrolled into an open labelarm of study NUC20904. Addition of 10 mg adefovir dipivoxil once daily to ongoing lamivudine100 mg for 52 weeks resulted in a median decrease in HBV DNA of 4.6 log10 copies/ml.

Improvement in liver function was also seen after one year of therapy. This degree of viral suppressionwas maintained (follow-on study NUC20917) with combined therapy during the second year oftreatment to week 104 and most patients had improved markers of liver function and continued toderive clinical benefit.

Experience in CHB patients with advanced fibrosis or cirrhosis:

In a placebo-controlled study in 651 patients with clinically compensated chronic hepatitis B andhistologically confirmed fibrosis or cirrhosis, lamivudine treatment (median duration 32 months)significantly reduced the rate of overall disease progression (34/436, 7.8 % for lamivudine versus38/215, 17.7 % for placebo, p=0.001), demonstrated by a significant reduction in the proportion ofpatients having increased Child-Pugh scores (15/436, 3.4 % versus 19/215, 8.8 %, p=0.023) ordeveloping hepatocellular carcinoma (17/436, 3.9 % versus 16/215, 7.4 %, p=0.047). The rate ofoverall disease progression in the lamivudine group was higher for subjects with detectable YMDDmutant HBV DNA (23/209, 11 %) compared to those without detectable YMDD mutant HBV(11/221, 5 %). However, disease progression in YMDD subjects in the lamivudine group was lowerthan the disease progression in the placebo group (23/209, 11 % versus 38/214, 18 % respectively).

Confirmed HBeAg seroconversion occurred in 47 % (118/252) of subjects treated with lamivudine and93 % (320/345) of subjects receiving lamivudine became HBV DNA negative (VERSANT [version1], bDNA assay, LLOD < 0.7 MEq/ml) during the study.

Experience in children and adolescents:

Lamivudine has been administered to children and adolescents with compensated CHB in a placebocontrolled study of 286 patients aged 2 to 17 years. This population primarily consisted of childrenwith minimal hepatitis B. A dose of 3 mg/kg once daily (up to a maximum of 100 mg daily) was usedin children aged 2 to 11 years and a dose of 100 mg once daily in adolescents aged 12 years and above.

This dose needs to be further substantiated. The difference in the HBeAg seroconversion rates (HBeAgand HBV DNA loss with HBeAb detection) between placebo and lamivudine was not statisticallysignificant in this population (rates after one year were 13 % (12/95) for placebo versus 22 % (42/191)for lamivudine; p=0.057). The incidence of YMDD mutant HBV was similar to that observed inadults, ranging from 19 % at week 52 up to 45 % in patients treated continuously for 24 months.

Lamivudine is well absorbed from the gastrointestinal tract, and the bioavailability of oral lamivudinein adults is normally between 80 and 85 %. Following oral administration, the mean time (Tmax) tomaximal serum concentrations (Cmax) is about an hour. At therapeutic dose levels i.e. 100 mg oncedaily, Cmax is in the order of 1.1-1.5 µg/ml and trough levels were 0.015-0.020 µg/ml.

Co-administration of lamivudine with food resulted in a delay of Tmax and a lower Cmax (decreased byup to 47 %). However, the extent (based on the AUC) of lamivudine absorbed was not influenced,therefore lamivudine can be administered with or without food.

From intravenous studies the mean volume of distribution is 1.3 l/kg. Lamivudine exhibits linearpharmacokinetics over the therapeutic dose range and displays low plasma protein binding to albumin.

Limited data shows lamivudine penetrates the central nervous system and reaches the cerebro-spinalfluid (CSF). The mean lamivudine CSF/serum concentration ratio 2-4 hours after oral administrationwas approximately 0.12.

Lamivudine is predominately cleared by renal excretion of unchanged substance. The likelihood ofmetabolic substance interactions with lamivudine is low due to the small (5-10 %) extent of hepaticmetabolism and the low plasma protein binding.

The mean systemic clearance of lamivudine is approximately 0.3 l/h/kg. The observed half-life ofelimination is 18 to 19 hours. The majority of lamivudine is excreted unchanged in the urine viaglomerular filtration and active secretion (organic cationic transport system). Renal clearance accountsfor about 70 % of lamivudine elimination.

Studies in patients with renal impairment show lamivudine elimination is affected by renaldysfunction. Dose reduction in patients with a creatinine clearance of < 50 ml/min is necessary (seesection 4.2).

The pharmacokinetics of lamivudine are unaffected by hepatic impairment. Limited data in patientsundergoing liver transplantation show that impairment of hepatic function does not impactsignificantly on the pharmacokinetics of lamivudine unless accompanied by renal dysfunction.

In elderly patients the pharmacokinetic profile of lamivudine suggests that normal ageing withaccompanying renal decline has no clinically significant effect on lamivudine exposure, except inpatients with creatinine clearance of < 50 ml/min (see section 4.2).

Administration of lamivudine in animal toxicity studies at high doses was not associated with anymajor organ toxicity. At the highest dosage levels, minor effects on indicators of liver and kidneyfunction were seen together with occasional reduction in liver weights. Reduction of erythrocytes andneutrophil counts were identified as the effects most likely to be of clinical relevance. These eventswere seen infrequently in clinical studies.

Lamivudine was not mutagenic in bacterial tests but, like many nucleoside analogues showed activityin an in vitro cytogenetic assay and the mouse lymphoma assay. Lamivudine was not genotoxic in vivoat doses that gave plasma concentrations around 60-70 times higher than the anticipated clinicalplasma levels. As the in vitro mutagenic activity of lamivudine could not be confirmed by in vivo tests,it is concluded that lamivudine should not represent a genotoxic hazard to patients undergoingtreatment.

Reproductive studies in animals have not shown evidence of teratogenicity and showed no effect onmale or female fertility. Lamivudine induces early embryolethality when administered to pregnantrabbits at exposure levels comparable to those achieved in man, but not in the rat even at very highsystemic exposures.

The results of long term carcinogenicity studies with lamivudine in rats and mice did not shown anycarcinogenic potential.

Microcrystalline cellulose

Sodium starch glycolate (Type A)

Magnesium stearate

Hypromellose 3cP

Hypromellose 6cP

Titanium dioxide

Macrogol 400

Polysorbate 80

Iron oxide yellow

Iron oxide red

Not applicable

2 years

This medicinal product does not require any special storage conditions.

White opaque PVC/PVdC - Aluminium blisters

Pack sizes of 28, 30, 84 or 100 film-coated tablets

Containers:

White opaque HDPE tablet containers with white opaque polyethylene child resistent screw cap withinduction seal

Pack size of 60 film-coated tablets

White opaque HDPE tablet containers with white opaque polypropylene child resistent, tamper-evident screw cap with induction seal

Pack size of 60 film-coated tablets

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Teva B.V.

Swensweg 52031GA Haarlem

Netherlands

EU/1/09/566/001- 28 Tablets

EU/1/09/566/002 - 30 Tablets

EU/1/09/566/003 - 84 Tablets

EU/1/09/566/004 - 100 Tablets

EU/1/09/566/005 - 60 Tablets (bottle)

EU/1/09/566/006 - 60 Tablets (bottle with tamper evident cap)

Date of first authorisation: 23 October 2009

Date of latest renewal: 09 September 2014

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu